The enzymatic addition and removal of acetyl groups at specific lysine residues comprise important biochemical reactions with a significant impact on many cellular processes.1 The addition of acetyl groups within histone proteins, the chief protein components of chromatin, is catalyzed by histone acetyltransferases (HAT), and histone deacetylases (HDAC) mediate the corresponding deacetylation reactions. The inhibition of the latter group of deacetylases has become a hot topic in medicinal chemistry, and the use of HDAC inhibitors (HDACIs) has found many applications with regard to cancer and CNS disorder therapies.2 In general, HDACIs act on 11 zinc-dependent HDAC isozymes, which are divided into four groups: class I (HDACs 1, 2, 3, 8), class IIa (HDACs 4, 5, 7, 9), class IIb (HDACs 6, 10), and class IV (HDAC11).3 The majority of known HDACIs primarily inhibit the class I enzymes, making them excellent candidates for cancer therapy applications, but other than class I HDACIs are normally required for the pursuit of non-oncology applications.4 Another important issue relates to the potential toxicity of compounds inhibiting multiple isozymes, as acetylation is involved in the control of many cellular processes and inhibition of some isozymes may cause undesirable side effects. Thus, the design and development of isozyme-selective inhibitors has emerged as an important challenge within the search for novel HDACIs.5 
In recent years, HDAC6 has been acknowledged as an attractive target for drug development,6 and an increasing number of research teams are currently involved in the quest for new compounds endowed with HDAC6 inhibitory activity.7 In addition to the potential of HDAC6-selective inhibitors for applications in the treatment of CNS disorders and neurodegenerative diseases, these compounds seem to provoke less side effects, hence the growing interest in their preparation.8 An important milestone in that respect concerns the identification of Tubacin as a selective HDAC6 inhibitor, although the application of this compound is hampered by its poor drug likeness and cumbrous synthesis.9 Since then, considerable advances have been made with regard to the preparation of new HDAC6 inhibitors, leading to an array of different molecular entities with improved chemical and pharmacological properties.7 From a chemical viewpoint, many of these molecules comprise the typical HDACI basic structure accommodating an aromatic cap group (surface recognition domain), a linker and a zinc-binding hydroxamic acid unit. A major breakthrough was accomplished recently, involving the rational design and synthesis of Tubastatin A as a novel and selective HDAC6 inhibitor.10 A later study by Kalin and coworkers observed that substitutions on the tetrahydrocarboline group of Tubastatin A analogues influence HDAC6 activity and selectivity.11 
Recent progress in the discovery of selective HDAC6 inhibitors at a molecular level has also shown that a branched sp2-hybridised carbon atom in a-position with respect to the hydroxamate ZBG gives rise to a good HDAC6 selectivity profile.12 This has been confirmed by different recently developed HDAC6 selective inhibitors with an N-hydroxybenzamide group in their molecular structure.13 Further HDAC6 selective inhibitors have been explored in e.g. WO2011/011186, WO2011/106632, WO2013/134467 and WO2014/147178.
Despite these promising results, the structural requirements for selective inhibition remain largely unknown. Some compounds have been reported to display relative HDAC6 selectivity or preferential HDAC6 inhibition. Despite much effort, truly selective compounds are few, and the precise structural determinants required to achieve the selective inhibition of single HDAC isozymes generally remain undefined.
There is thus still a need in the art for novel HDACIs, and particularly selective HDAC6 inhibitors, that are useful in the treatment of diseases wherein HDAC inhibition provides a benefit, such as a cell proliferative disease, an autoimmune or inflammatory disorder, a neurodegenerative disease, a viral disease, malaria, or a combination thereof. Accordingly, a significant need exists in the art for efficacious compounds, compositions, and methods useful in the treatment of such diseases, alone or in conjunction with other therapies used to treat these diseases and conditions. The present invention is directed to meeting this need.